Stereoselective synthesis of syn-β-amino esters using the TiCl 4/R3N reagent system

Article abstract of DOI:10.1016/j.tetlet.2005.06.048

The reactions of benzaldehyde imines and esters with the TiCl ₄/R₃N reagent system give syn-β-amino esters as the major products in 38-87% yields.

Full text of DOI:10.1016/j.tetlet.2005.06.048

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5521–5524
Stereoselective synthesis of syn-b-amino esters using the
TiCl4/R3N reagent system
Mariappan Periasamy,* Surisetti Suresh and Subramaniapillai Selva Ganesan
School of Chemistry, University of Hyderabad, Central University PO, Hyderabad 500 046, India
Received 24 March 2005; revised 1 June 2005; accepted 10 June 2005
Available online 1 July 2005
Dedicated to Dr. A. V. Rama Rao on the occasion of his 70th birthday
Abstract—The reactions of benzaldehyde imines and esters with the TiCl4/R3N reagent system give syn-b-amino esters as the major
products in 38–87% yields.
Ó 2005 Published by Elsevier Ltd.
b-Amino acid moieties are present in several biologi-
cally important compounds1 and they are useful as
building blocks for b-lactams2 and b-peptides3 that are
present in several drugs.4 Hence, there is interest in
developing convenient methods for the synthesis of
b-amino esters. In recent years, the Mannich reaction5
and its variants have been used in key steps in the syn-
thesis of several biologically and pharmacologically
important compounds.6 Mannich-type reactions have
also been used in the synthesis of b-amino esters. For
example, the Lewis acid promoted additions of silyl es-
ter enolates7 and lithium ester enolates8 are widely used
for the synthesis of b-amino esters. Previously, ester
enolates of titanium, prepared using the corresponding
silyl9 or lithium10 enolates, were used in Mannich
reactions with aldimines. Afew reports describe the
Mannich reactions of titanium enolates, prepared
directly from esters and amides using TiCl4/NR3, with
imines. In these cases, the corresponding anti-b-amino
carbonyl compounds were obtained as the major prod-
ucts and the substrates contained an additional coordi-
nating moiety.11 During investigations on synthetic
applications of the TiCl4/R3N reagent system,12,13 we
observed syn selectivity in the formation of b-amino
esters from benzaldehyde imines and simple esters not
containing any additional coordinating groups. These
results are described herein.
We have observed that esters and imines react with the
TiCl4/tertiary amine reagent system to give the corre-
sponding syn-b-amino esters in good yields. Initially,
the experiments were carried out using methyl butyrate
1a, N-benzylidene benzylamine 2a and TiCl4 in combi-
nation with different tertiary amines such as Et3N,
i-Pr2NEt, n-Bu3N and TMEDA. The titanium ester
enolate was prepared in situ by adding TiCl4 to the ester
at ꢀ45 °C followed by the addition of the 3° amine. It
was observed that the TiCl4/Et3N reagent system gave
the corresponding b-amino ester 3a in excellent yields
(Eq. 1). Interestingly, only one of the possible diastereo-
mers was formed as the major product.
We then examined this transformation with different
esters and imines (Eq. 2, Table 1).
In the reaction of methyl butyrate and imines derived
from alkylamines and benzaldehyde the selectivities as
well as the yields were high (entries 1–3), whereas the
imine derived from aniline and benzaldehyde gave a
poor yield (38% entry 4). In the reaction of the imine
prepared from (R)-a-methylbenzylamine and benzalde-
hyde with methyl butyrate, the chiral b-amino ester 3c
was obtained in 82% yield. An X-ray single crystal struc-
ture analysis of the corresponding 3,5-dinitrobenzamide
derivative 5 (Eq. 3) revealed that the major isomer pos-
sesses syn stereochemistry (Fig. 1).14 Furthermore, the
absolute configurations of the newly formed chiral cen-
tres were assigned as S,S based on the X-ray data.
Keywords: b-Amino esters; Titanium ester enolates; Imines and Man-
nich reaction.
*
Corresponding author. Tel.: +91 40 23134814; fax: +91 40
23012460; e-mail: mpsc@uohyd.ernet.in
0040-4039/$ - see front matter Ó 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2005.06.048

5522
M. Periasamy et al. / Tetrahedron Letters 46 (2005) 5521–5524
NHBn
1. TiCl4, -45oC, CH2Cl2, 0.5 h
NBn
MeOOC
MeOOC
+
Ph
2. R3N, -45oC-rt, 3 h
Ph
C2H5
1a
C2H5
ð1Þ
2a
3a
amine = Et3N - 87%, nBu3N - 33%
amine = iPr2NEt - 21%, TMEDA - 0%
NHR2
Ph
NHR2
Ph
NR2
Ph
2a-d
1. TiCl4/CH2Cl2
2. Et3N
MeOOC
MeOOC
MeOOC
+
+
R1
1a-b
R1
3a-g
syn (major)
R1
3a-g
anti (minor)
ð2Þ
Table 1. Reactions of esters and imines with the TiCl4/Et3N reagent system
Entry
R1
R2
Temperature (°C)
% Yield of 3a
syn/anti
1
2
3
4
5
6
7
Et
Et
Et
Et
Ph
Ph
Ph
Bn
n-Bu
ꢀ45
ꢀ45
ꢀ45
ꢀ45
0
(3a) 87
(3b) 78
(3c) 82b,c
(3d) 38
(3e) 78b
(3f) 80
100:0d,e
95:5d,e
92:8e
55:45d,e
73:27g
66:34f,g
67:33e,f
CH(Ph)CH3
Ph
Bn
n-Bu
Ph
0
0
(3g) 41
a The structures of the products were confirmed by spectral data (IR, 1H NMR and 13C NMR) and mass and elemental analyses (see Supplementary
data). Yields are for isolated products.
b The syn stereochemistry was assigned to the major diastereomers of the products 3c and 3e based on the crystal structures of their derivatives 5 and
6, respectively.
c This imine was prepared from (R)-a-methylbenzylamine and benzaldehyde. The stereochemistry of the new chiral centres was assigned (S,S) on the
basis of crystal structure analysis of the derivative 5 prepared using 3c.
d The stereochemistry of the major products 3a,b and 3d was assigned as syn by comparison of 1H NMR data with those of 3c.
e The syn/anti ratio was determined by 13C NMR (50 MHz) data.
f The stereochemistry of the major products 3f and 3g was assigned as syn by comparison of 1H NMR data with those of 3e.
g The syn/anti ratio is the ratio of the diastereomers separated using column chromatography.
NO2
Ph
CH3
Ph
O
COCl
O2N
HN
Ph
CH3
Pyridine/THF
reflux, 6 h
MeOOC
ð3Þ
N
+
O2N
MeOOC
NO2
C2H5
Ph
C2H5
3c
4
(S,S,R)-5 74%
The stereochemistries of the major products 3a,b and 3d
were assigned as syn by comparison of their H NMR
data with those of compound 3c.
In the cases of b-amino esters prepared from methyl
phenylacetate, the diastereomers were separable by col-
umn chromatography. We observed that the imines pre-
1

M. Periasamy et al. / Tetrahedron Letters 46 (2005) 5521–5524
5523
aniline and benzaldehyde gave a poor yield (41% entry
7). An X-ray analysis of the complex 6 prepared from
the major isomer of b-aminoester 3e and oxalic acid
revealed that the product had the syn stereochemistry
(Fig. 2).15
The stereochemistries of the major isomers of products
3f and 3g were assigned as syn by comparison of H
1
NMR data with those of compound 3e. The syn stereo-
selectivity for the products can be tentatively explained
on the basis of the stereochemical argument is shown
in Figure 3. The configuration of the imine is expected
to be E.16 The results can be explained considering that
the E-titanium ester enolate would be in equilibrium
with the Z-titanium ester enolate. The reaction of the
E-titanium ester enolate would give a low energy transi-
tion state TS-1 leading to the major syn product,
whereas the Z-titanium ester enolate would result in a
high energy transition state TS-2 leading to the minor
anti product.
Figure 1. ORTEP representation of the crystal structure of compound
5 (thermal ellipsoids are drawn at 20% probability).
b-Amino acid moieties are present in several biologically
important compounds such as dolastins, astins, onchi-
din, jasplakinolide and motuporin.1 Also, it is notewor-
thy that certain biologically active molecules like taxol,
bestatin, kynostatins, scytonemyn Aand microginin
contain syn configured b-amino acid moieties.1 Hence,
the method described here for the synthesis of syn-b-
amino esters using the TiCl4/R3N reagent system has
good synthetic potential.
Acknowledgements
Figure 2. ORTEP representation of the crystal structure of the
complex of 3e with oxalic acid (thermal ellipsoids are drawn at 20%
probability).
We thank the CSIR (New Delhi) for financial support.
We are also grateful to the UGC for support under
the ÔUniversity with Potential for ExcellenceÕ program.
We thank the DST for use of the National single crystal
X-ray diffractometer facility.
pared from alkyl amines and benzaldehyde gave good
yields (entries 5 and 6) and that the imine prepared from
NHR2
LnTi
R2
R2
H
NH
O
N
MeOOC
Ph
R1
Ph
H
MeOOC
H
MeO
R1
syn (major)
Ph
H
R1
E-imine and E-enolate
TS-1
NHR2
LnTi
R2
R2
H
NH
O
N
MeOOC
Ph
H
R1
H
Ph
R1
MeOOC
MeO
R1
anti (minor)
Ph
H
E-imine and Z-enolate
TS-2
Figure 3. Stereochemical models.

5524
M. Periasamy et al. / Tetrahedron Letters 46 (2005) 5521–5524
Gennari, C.; Venturini, I.; Gislon, G.; Schimperna, G.
Tetrahedron Lett. 1987, 28, 227–230.
Supplementary data
10. (a) Fujisawa, T.; Ukaji, Y.; Noro, T.; Date, K.; Shimizu,
M. Tetrahedron Lett. 1991, 32, 7563–7566; (b) Fujisawa,
T.; Ichikawa, M.; Ukaji, Y.; Shimizu, M. Tetrahedron
Lett. 1993, 34, 1307–1310; (c) Lazzaro, F.; Crucianelli, M.;
De Angelis, F.; Frigerio, M.; Malpezzi, L.; Volonterio, A.;
Zanda, M. Tetrahedron: Asymmetry 2004, 15, 889–
893.
Supplementary data associated with this article can be
found, in the online version at doi:10.1016/j.tetlet.2005.
06.048.
References and notes
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14. Crystal Data: For compound 5: molecular formula:
C27H27N3O7, MW = 505.52, monoclinic, space group:
˚
P2(1), a = 11.3587(8) A, b = 6.7522(5) A, c = 17.6162(12) A,
˚
˚
3
˚
b = 107.5420(10)°, V = 1288.26(16) A , Z = 2, qc = 1.303
mg mꢀ3, l = 0.09 mmꢀ1, T = 293(2) K. Of the 5792 reflec-
tions collected, 3877 were unique (Rint = 0.0000). Refine-
ment on all data converged at R1 = 0.0490, wR2 = 0.0830.
(Deposition number CCDC 265595.)
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oxalic acid (3 mmol) were dissolved in dry acetone (8 mL)
and the solution was stirred for 6 h. The precipitate was
filtered off and crystallized from acetonitrile to obtain
crystals suitable for X-ray analysis.
Crystal Data: Complex of the amino ester 3e and
oxalic acid: molecular formula: C25H25NO6, MW =
˚
438.48, monoclinic, space group: P2(1)/n, a = 6.0118(6) A,
˚
˚
b = 15.7611(16) A, c = 21.550(2) A, b = 96.979(2)°, V =
2026.8(3) A , Z = 4, qc = 1.437 mg mꢀ3, l = 0.103 mmꢀ1
,
3
˚
T = 293(2) K. Of the 4878 reflections collected, 2855 were
unique (Rint = 0.0000). Refinement on all data converged at
R1 = 0.0517, wR2 = 0.1085. (Deposition number CCDC
265594.)
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